Mucopolysaccharidosis type I (MPS I) is a progressive multisystem disorder with features ranging over a continuum of severity. While affected individuals have traditionally been classified as having one of three MPS I syndromes (Hurler syndrome, Hurler-Scheie syndrome, or Scheie syndrome), no easily measurable biochemical differences have been identified and the clinical findings overlap. Affected individuals are best described as having either a phenotype consistent with either severe (Hurler syndrome) or attenuated MPS I, a distinction that influences therapeutic options. Severe MPS I. Infants appear normal at birth. Typical early manifestations are nonspecific (e.g., umbilical or inguinal hernia, frequent upper respiratory tract infections before age 1 year). Coarsening of the facial features may not become apparent until after age one year. Gibbus deformity of the lower spine is common and often noted within the first year. Progressive skeletal dysplasia (dysostosis multiplex) involving all bones is universal, as is progressive arthropathy involving most joints. By age three years, linear growth decreases. Intellectual disability is progressive and profound but may not be readily apparent in the first year of life. Progressive cardiorespiratory involvement, hearing loss, and corneal clouding are common. Without treatment, death (typically from cardiorespiratory failure) usually occurs within the first ten years of life. Attenuated MPS I. Clinical onset is usually between ages three and ten years. The severity and rate of disease progression range from serious life-threatening complications leading to death in the second to third decade, to a normal life span complicated by significant disability from progressive joint manifestations and cardiorespiratory disease. While some individuals have no neurologic involvement and psychomotor development may be normal in early childhood, learning disabilities and psychiatric manifestations can be present later in life. Hearing loss, cardiac valvular disease, respiratory involvement, and corneal clouding are common.

Hypohidrotic ectodermal dysplasia (HED) is characterized by hypotrichosis (sparseness of scalp and body hair), hypohidrosis (reduced ability to sweat), and hypodontia (congenital absence of teeth). The cardinal features of classic HED become obvious during childhood. The scalp hair is thin, lightly pigmented, and slow growing. Sweating, although present, is greatly deficient, leading to episodes of hyperthermia until the affected individual or family acquires experience with environmental modifications to control temperature. Only a few abnormally formed teeth erupt, at a later-than-average age. Physical growth and psychomotor development are otherwise within normal limits. Mild HED is characterized by mild manifestations of any or all the characteristic features.

Williams syndrome (WS) is characterized by cardiovascular disease (elastin arteriopathy, peripheral pulmonary stenosis, supravalvar aortic stenosis, hypertension), distinctive facies, connective tissue abnormalities, intellectual disability (usually mild), a specific cognitive profile, unique personality characteristics, growth abnormalities, and endocrine abnormalities (hypercalcemia, hypercalciuria, hypothyroidism, and early puberty). Feeding difficulties often lead to poor weight gain in infancy. Hypotonia and hyperextensible joints can result in delayed attainment of motor milestones.

The Marshall-Smith syndrome (MRSHSS) is a malformation syndrome characterized by accelerated skeletal maturation, relative failure to thrive, respiratory difficulties, mental retardation, and unusual facies, including prominent forehead, shallow orbits, blue sclerae, depressed nasal bridge, and micrognathia (Adam et al., 2005).

Trichodentoosseous syndrome (TDO) is an autosomal dominant disorder with complete penetrance characterized by abnormalities involving hair, teeth, and bone (summary by Nguyen et al., 2013).

Keratitis-ichthyosis-deafness (KID) syndrome is a rare ectodermal dysplasia characterized by sensorineural hearing loss, photophobia and corneal vascularization, hyperkeratosis of the palms and soles, erythrokeratoderma, follicular hyperkeratosis, and recurrent bacterial and fungal infections. A subset of patients with KID may develop multiple cystic pilar tumors, which are prone to malignant transformation and metastasis (Nyquist et al., 2007). Vohwinkel syndrome (124500) is an allelic disorder involving congenital deafness with keratopachydermia and constrictions of fingers and toes. Another similar disorder caused by mutation in GJB2 is palmoplantar keratoderma with deafness (148350). Genetic Heterogeneity of Keratitis-Ichthyosis-Deafness Syndrome An autosomal recessive form of KID syndrome (KIDAR; 242150) is caused by mutation in the AP1B1 gene (600157) on chromosome 22q12.

In dentin dysplasia type I, both primary and secondary dentitions are affected. The color and general morphology of the teeth are usually normal, although they may be slightly opalescent and blue or brown. Teeth may be very mobile and exfoliate spontaneously because of inadequate root formation. On radiographs, the roots are short and may be more pointed than normal. Pulp chambers are usually absent except for a chevron-shaped remnant in the crown (Witkop, 1975). Root canals are usually absent. Periapical radiolucencies may be present at the apices of affected teeth, for reasons unknown. On light microscopic examination of the permanent teeth, the coronal dentin is normal, but further apically becomes irregular, fills the pulp chamber, and has a 'sand-dune' morphology. Scanning electron microscopic studies of the deciduous and permanent teeth have been reported (Sauk et al., 1972; Melnick et al., 1980). Subclassification of Dentin Dysplasia Type I O Carroll et al. (1991) and O Carroll and Duncan (1994) reviewed dentin dysplasia and proposed 4 subtypes of dentin dysplasia type I, which they designated as DD1a-d. In DD1a, there is complete obliteration of pulp chambers and no root development, with many periapical radiolucent areas. In DD1b, there are horizontal crescent-shaped radiolucent pulpal remnants and a few millimeters of root development, with many periapical radiolucent areas. DD1c shows 2 horizontal crescent-shaped radiolucent lines and significant but incomplete root development, with or without periapical radiolucent areas. DD1d is characterized by visible pulp chambers and oval pulp stones in the coronal third of the root canal with bulging of the root around the stones and few if any periapical radiolucent areas. The authors noted that the distinctions between the subtypes of DD1 were primarily useful clinically in terms of treatment options.

ATP6V0A2-related cutis laxa is characterized by generalized cutis laxa, findings associated with generalized connective tissue disorder, developmental delays, and a variety of neurologic findings including abnormality on brain MRI. At birth, hypotonia, overfolded skin, and distinctive facial features are present and enlarged fontanelles are often observed. During childhood, the characteristic facial features and thick or coarse hair may become quite pronounced. The skin findings decrease with age, although easy bruising and Ehlers-Danlos-like scars have been described in some. In most (not all) affected individuals, cortical and cerebellar malformations are observed on brain MRI. Nearly all affected individuals have developmental delays, seizures, and neurologic regression.

Abnormalities of the digits can affect both the fingers and the toes in people with oral-facial-digital syndrome. These abnormalities include fusion of certain fingers or toes (syndactyly), digits that are shorter than usual (brachydactyly), or digits that are unusually curved (clinodactyly). The presence of extra digits (polydactyly) is also seen in most forms of oral-facial-digital syndrome.\n\nDistinctive facial features often associated with oral-facial-digital syndrome include a split in the lip (a cleft lip); a wide nose with a broad, flat nasal bridge; and widely spaced eyes (hypertelorism).\n\nAbnormalities of the oral cavity that occur in many types of oral-facial-digital syndrome include a split (cleft) in the tongue, a tongue with an unusual lobed shape, and the growth of noncancerous tumors or nodules on the tongue. Affected individuals may also have extra, missing, or defective teeth. Another common feature is an opening in the roof of the mouth (a cleft palate). Some people with oral-facial-digital syndrome have bands of extra tissue (called hyperplastic frenula) that abnormally attach the lip to the gums.\n\nThe signs and symptoms of oral-facial-digital syndrome vary widely. However, most forms of this disorder involve problems with development of the oral cavity, facial features, and digits. Most forms are also associated with brain abnormalities and some degree of intellectual disability.\n\nResearchers have identified at least 13 potential forms of oral-facial-digital syndrome. The different types are classified by their patterns of signs and symptoms. However, the features of the various types overlap significantly, and some types are not well defined. The classification system for oral-facial-digital syndrome continues to evolve as researchers find more affected individuals and learn more about this disorder.\n\nOther features occur in only one or a few types of oral-facial digital syndrome. These features help distinguish the different forms of the disorder. For example, the most common form of oral-facial-digital syndrome, type I, is associated with polycystic kidney disease. This kidney disease is characterized by the growth of fluid-filled sacs (cysts) that interfere with the kidneys' ability to filter waste products from the blood. Other forms of oral-facial-digital syndrome are characterized by neurological problems, particular changes in the structure of the brain, bone abnormalities, vision loss, and heart defects.\n\nOral-facial-digital syndrome is actually a group of related conditions that affect the development of the oral cavity (the mouth and teeth), facial features, and digits (fingers and toes).

Trichorhinophalangeal syndrome (TRPS) comprises TRPS I (caused by a heterozygous pathogenic variant in TRPS1) and TRPS II (caused by contiguous gene deletion of TRPS1, RAD21, and EXT1). Both types of TRPS are characterized by distinctive facial features; ectodermal features (fine, sparse, depigmented, and slow growing hair; dystrophic nails; and small breasts); and skeletal findings (short stature; short feet; brachydactyly with ulnar or radial deviation of the fingers; and early, marked hip dysplasia). TRPS II is characterized by multiple osteochondromas (typically first observed clinically on the scapulae and around the elbows and knees between ages 1 month and 6 years) and an increased risk of mild-to-moderate intellectual disability.

Cranioectodermal dysplasia (CED) is a ciliopathy with skeletal involvement (narrow thorax, shortened proximal limbs, syndactyly, polydactyly, brachydactyly), ectodermal features (widely spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity, abnormal nails), joint laxity, growth deficiency, and characteristic facial features (frontal bossing, low-set simple ears, high forehead, telecanthus, epicanthal folds, full cheeks, everted lower lip). Most affected children develop nephronophthisis that often leads to end-stage kidney disease in infancy or childhood, a major cause of morbidity and mortality. Hepatic fibrosis and retinal dystrophy are also observed. Dolichocephaly, often secondary to sagittal craniosynostosis, is a primary manifestation that distinguishes CED from most other ciliopathies. Brain malformations and developmental delay may also occur.

Microcephalic osteodysplastic primordial dwarfism type II (MOPDII), the most common form of microcephalic primordial dwarfism, is characterized by extreme short stature and microcephaly along with distinctive facial features. Associated features that differentiate it from other forms of primordial dwarfism and that may necessitate treatment include: abnormal dentition, a slender bone skeletal dysplasia with hip deformity and/or scoliosis, insulin resistance / diabetes mellitus, chronic kidney disease, cardiac malformations, and global vascular disease. The latter includes neurovascular disease such as moyamoya vasculopathy and intracranial aneurysms (which can lead to strokes), coronary artery disease (which can lead to premature myocardial infarctions), and renal vascular disease. Hypertension, which is also common, can have multiple underlying causes given the complex comorbidities.

Floating-Harbor syndrome (FHS) is characterized by typical craniofacial features; low birth weight, normal head circumference, and short stature; bone age delay that normalizes between ages six and 12 years; skeletal anomalies (brachydactyly, clubbing, clinodactyly, short thumbs, prominent joints, clavicular abnormalities); severe receptive and expressive language impairment; hypernasality and high-pitched voice; and intellectual disability that is typically mild to moderate. Difficulties with temperament and behavior that are present in many children tend to improve in adulthood. Other features can include hyperopia and/or strabismus, conductive hearing loss, seizures, gastroesophageal reflux, renal anomalies (e.g., hydronephrosis / renal pelviectasis, cysts, and/or agenesis), and genital anomalies (e.g., hypospadias and/or undescended testes).

Filippi syndrome is characterized by short stature, microcephaly, syndactyly, intellectual disability, and facial dysmorphism consisting of bulging forehead, broad and prominent nasal bridge, and diminished alar flare. Common features include cryptorchidism, speech impairment, and clinodactyly of the fifth finger, Some patients exhibit visual disturbances, polydactyly, seizures, and/or ectodermal abnormalities, such as nail hypoplasia, long eyelashes, hirsutism, and microdontia (summary by Hussain et al., 2014).

Oculodentodigital syndrome is characterized by a typical facial appearance and variable involvement of the eyes, dentition, and fingers. Characteristic facial features include a narrow, pinched nose with hypoplastic alae nasi, prominent columella and thin anteverted nares together with a narrow nasal bridge, and prominent epicanthic folds giving the impression of hypertelorism. The teeth are usually small and carious. Typical eye findings include microphthalmia and microcornea. The characteristic digital malformation is complete syndactyly of the fourth and fifth fingers (syndactyly type III) but the third finger may be involved and associated camptodactyly is a common finding (summary by Judisch et al., 1979). Neurologic abnormalities are sometimes associated (Gutmann et al., 1991), and lymphedema has been reported in some patients with ODDD (Brice et al., 2013). See review by De Bock et al. (2013). Genetic Heterogeneity of Oculodentodigital Syndrome An autosomal recessive form of ODDD (257850) is also caused by mutation in the GJA1 gene, but the majority of cases are autosomal dominant.

Schimke immunoosseous dysplasia (SIOD) is characterized by spondyloepiphyseal dysplasia (SED) resulting in short stature, nephropathy, and T-cell deficiency. Radiographic manifestations of SED include ovoid and mildly flattened vertebral bodies, small ilia with shallow dysplastic acetabular fossae, and small deformed capital femoral epiphyses. Nearly all affected individuals have progressive steroid-resistant nephropathy, usually developing within five years of the diagnosis of growth failure and terminating with end-stage renal disease. The majority of tested individuals have T-cell deficiency and an associated risk for opportunistic infection, a common cause of death. SIOD involves a spectrum that ranges from an infantile or severe early-onset form with a greater risk of death during childhood to a juvenile or milder later-onset form with likely survival into adulthood if renal disease is appropriately treated.

The TP63-related disorders comprise six overlapping phenotypes: Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome (which includes Rapp-Hodgkin syndrome). Acro-dermo-ungual-lacrimal-tooth (ADULT) syndrome. Ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3). Limb-mammary syndrome. Split-hand/foot malformation type 4 (SHFM4). Isolated cleft lip/cleft palate (orofacial cleft 8). Individuals typically have varying combinations of ectodermal dysplasia (hypohidrosis, nail dysplasia, sparse hair, tooth abnormalities), cleft lip/palate, split-hand/foot malformation/syndactyly, lacrimal duct obstruction, hypopigmentation, hypoplastic breasts and/or nipples, and hypospadias. Findings associated with a single phenotype include ankyloblepharon filiforme adnatum (tissue strands that completely or partially fuse the upper and lower eyelids), skin erosions especially on the scalp associated with areas of scarring, and alopecia, trismus, and excessive freckling.

Axenfeld-Rieger syndrome is a disorder of morphogenesis that results in abnormal development of the anterior segment of the eye, which results in blindness from glaucoma in approximately 50% of affected individuals. Systemic abnormalities, including cardiac and dental anomalies, are associated. For a general phenotypic description and a discussion of genetic heterogeneity and nomenclature of Axenfeld-Rieger syndrome, see RIEG1 (180500).

Dental anomalies and short stature (DASS) is characterized by significant short stature with brachyolmia as well as hypoplastic amelogenesis imperfecta with almost absent enamel (Huckert et al., 2015). Some patients exhibit valvular and/or vascular defects, including mitral valve prolapse, aortic root dilation, and aortic as well as other arterial aneurysms (Dugan et al., 2015; Guo et al., 2018). Inter- and intrafamilial variability has been reported.

The first identified CACNA1C-related disorder, referred to as Timothy syndrome, consists of the combination of prolonged QT interval, autism, and cardiovascular malformation with syndactyly of the fingers and toes. Infrequent findings also include developmental and speech delay, seizures, and recurrent infections. With increased availability of molecular genetic testing, a wider spectrum of pathogenic variants and clinical findings associated with CACNA1C-related disorders has been recognized. Because CACNA1C is associated with calcium channel function, all individuals with a pathogenic variant in this gene are at risk for cardiac arrhythmia of a specific type. The clinical manifestations of a CACNA1C-related disorder include three phenotypes: Timothy syndrome with or without syndactyly. QT prolongation (QTc >480 ms) and arrhythmias in the absence of other syndromic features. Short QT syndrome (QTc <350 ms) or Brugada syndrome with short QT interval. These three phenotypes can be separated into two broad categories on the basis of the functional consequences of the pathogenic variants in CACNA1C: QT prolongation with or without a Timothy syndrome-associated phenotype associated with pathogenic variants inducing a gain of function at the cellular level (i.e., increased calcium current). Short QT interval with or without Brugada syndrome EKG pattern associated with pathogenic variants causing loss of function (i.e., reduced calcium current).

CHST3-related skeletal dysplasia is characterized by short stature of prenatal onset, joint dislocations (knees, hips, radial heads), clubfeet, and limitation of range of motion that can involve all large joints. Kyphosis and occasionally scoliosis with slight shortening of the trunk develop in childhood. Minor heart valve dysplasia has been described in several persons. Intellect and vision are normal.

Seckel syndrome is a rare autosomal recessive disorder characterized by growth retardation, microcephaly with mental retardation, and a characteristic facial appearance (Borglum et al., 2001). For a general phenotypic description and a discussion of genetic heterogeneity of Seckel syndrome, see SCKL1 (210600).

Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by Huber and Cormier-Daire, 2012 and Schmidts et al., 2013). There is phenotypic overlap with the cranioectodermal dysplasias (Sensenbrenner syndrome; see CED1, 218330). For a discussion of genetic heterogeneity of short-rib thoracic dysplasia, see SRTD1 (208500).

Abnormal hair, joint laxity, and developmental delay (HJDD) is characterized by normal hair at birth that gradually becomes sparse, twisted, brittle, and easily broken, with pili torti and trichorrhexis nodosa observed on light microscopy. Other features include increased joint mobility and cognitive delay (Sharma et al., 2019).

Raine syndrome (RNS) is a neonatal osteosclerotic bone dysplasia of early and aggressive onset that usually results in death within the first few weeks of life, although there have been some reports of survival into childhood. Radiographic studies show a generalized increase in the density of all bones and a marked increase in the ossification of the skull. The increased ossification of the basal structures of the skull and facial bones underlies the characteristic facial features, which include narrow prominent forehead, proptosis, depressed nasal bridge, and midface hypoplasia. Periosteal bone formation is also characteristic of this disorder and differentiates it from osteopetrosis and other known lethal and nonlethal osteosclerotic bone dysplasias. The periosteal bone formation typically extends along the diaphysis of long bones adjacent to areas of cellular soft tissue (summary by Simpson et al., 2009). Some patients survive infancy (Simpson et al., 2009; Fradin et al., 2011).

An EEC syndrome characterized by autosomal dominant inheritance that has material basis in variation in the chromosome region 7q11.2-q21.3.

Cornelia de Lange syndrome (CdLS) encompasses a spectrum of findings from mild to severe. Severe (classic) CdLS is characterized by distinctive facial features, growth restriction (prenatal onset; <5th centile throughout life), hypertrichosis, and upper-limb reduction defects that range from subtle phalangeal abnormalities to oligodactyly (missing digits). Craniofacial features include synophrys, highly arched and/or thick eyebrows, long eyelashes, short nasal bridge with anteverted nares, small widely spaced teeth, and microcephaly. Individuals with a milder phenotype have less severe growth, cognitive, and limb involvement, but often have facial features consistent with CdLS. Across the CdLS spectrum IQ ranges from below 30 to 102 (mean: 53). Many individuals demonstrate autistic and self-destructive tendencies. Other frequent findings include cardiac septal defects, gastrointestinal dysfunction, hearing loss, myopia, and cryptorchidism or hypoplastic genitalia.

Congenital deafness with labyrinthine aplasia, microtia, and microdontia (LAMM syndrome) is characterized by: profound bilateral congenital sensorineural deafness associated with inner ear anomalies (most often bilateral complete labyrinthine aplasia); microtia (type I) that is typically bilateral (although unilateral microtia and normal external ears are observed on occasion); and microdontia (small teeth). Individuals with LAMM syndrome commonly have motor delays during infancy presumably due to impaired balance from inner ear (vestibular) abnormalities. Growth, physical development, and cognition are normal.

Temtamy preaxial brachydactyly syndrome (TPBS) is an autosomal recessive disorder characterized by bilateral, symmetric preaxial brachydactyly and hyperphalangism of digits, facial dysmorphism, dental anomalies, sensorineural hearing loss, delayed motor and mental development, and growth retardation (summary by Li et al., 2010).

EEM syndrome denotes a disorder characterized by ectodermal dysplasia, ectrodactyly, and macular dystrophy. The ectodermal dysplasia consists of hypotrichosis affecting scalp hair, eyebrows, and eyelashes, with partial anodontia. Different degrees of absence deformities as well as syndactyly have been described, the hands often being more severely affected than the feet. The retinal lesion appears as a central geographic atrophy of the retinal pigment epithelium and choriocapillary layer of the macular area with coarse hyperpigmentations and sparing of the larger choroidal vessels (summary by Kjaer et al., 2005).

Dyskeratosis congenita and related telomere biology disorders (DC/TBD) are caused by impaired telomere maintenance resulting in short or very short telomeres. The phenotypic spectrum of telomere biology disorders is broad and includes individuals with classic dyskeratosis congenita (DC) as well as those with very short telomeres and an isolated physical finding. Classic DC is characterized by a triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia, although this may not be present in all individuals. People with DC/TBD are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome or acute myelogenous leukemia, solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis. Other findings can include eye abnormalities (epiphora, blepharitis, sparse eyelashes, ectropion, entropion, trichiasis), taurodontism, liver disease, gastrointestinal telangiectasias, and avascular necrosis of the hips or shoulders. Although most persons with DC/TBD have normal psychomotor development and normal neurologic function, significant developmental delay is present in both forms; additional findings include cerebellar hypoplasia (Hoyeraal Hreidarsson syndrome) and bilateral exudative retinopathy and intracranial calcifications (Revesz syndrome and Coats plus syndrome). Onset and progression of manifestations of DC/TBD vary: at the mild end of the spectrum are those who have only minimal physical findings with normal bone marrow function, and at the severe end are those who have the diagnostic triad and early-onset BMF.

The TP63-related disorders comprise six overlapping phenotypes: Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome (which includes Rapp-Hodgkin syndrome). Acro-dermo-ungual-lacrimal-tooth (ADULT) syndrome. Ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3). Limb-mammary syndrome. Split-hand/foot malformation type 4 (SHFM4). Isolated cleft lip/cleft palate (orofacial cleft 8). Individuals typically have varying combinations of ectodermal dysplasia (hypohidrosis, nail dysplasia, sparse hair, tooth abnormalities), cleft lip/palate, split-hand/foot malformation/syndactyly, lacrimal duct obstruction, hypopigmentation, hypoplastic breasts and/or nipples, and hypospadias. Findings associated with a single phenotype include ankyloblepharon filiforme adnatum (tissue strands that completely or partially fuse the upper and lower eyelids), skin erosions especially on the scalp associated with areas of scarring, and alopecia, trismus, and excessive freckling.

The TP63-related disorders comprise six overlapping phenotypes: Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome (which includes Rapp-Hodgkin syndrome). Acro-dermo-ungual-lacrimal-tooth (ADULT) syndrome. Ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3). Limb-mammary syndrome. Split-hand/foot malformation type 4 (SHFM4). Isolated cleft lip/cleft palate (orofacial cleft 8). Individuals typically have varying combinations of ectodermal dysplasia (hypohidrosis, nail dysplasia, sparse hair, tooth abnormalities), cleft lip/palate, split-hand/foot malformation/syndactyly, lacrimal duct obstruction, hypopigmentation, hypoplastic breasts and/or nipples, and hypospadias. Findings associated with a single phenotype include ankyloblepharon filiforme adnatum (tissue strands that completely or partially fuse the upper and lower eyelids), skin erosions especially on the scalp associated with areas of scarring, and alopecia, trismus, and excessive freckling.

KAT6B disorders include genitopatellar syndrome (GPS) and Say-Barber-Biesecker-Young-Simpson variant of Ohdo syndrome (SBBYSS) which are part of a broad phenotypic spectrum with variable expressivity; individuals presenting with a phenotype intermediate between GPS and SBBYSS have been reported. Both phenotypes are characterized by some degree of global developmental delay / intellectual disability; hypotonia; genital abnormalities; and skeletal abnormalities including patellar hypoplasia/agenesis, flexion contractures of the knees and/or hips, and anomalies of the digits, spine, and/or ribs. Congenital heart defects, small bowel malrotation, feeding difficulties, slow growth, cleft palate, hearing loss, and dental anomalies have been observed in individuals with either phenotype.

MBD5 haploinsufficiency is a neurodevelopmental disorder characterized by developmental delay, intellectual disability, severe speech impairment, seizures, sleep disturbances, and abnormal behaviors. Most children lack speech entirely or have single words, short phrases, or short sentences. Seizures are present in more than 80% of children; onset is usually around age two years. Sleep disturbances, present in about 90%, can result in excessive daytime drowsiness. Abnormal behaviors can include autistic-like behaviors (80%) and self-injury and aggression (>60%).

Any tooth agenesis in which the cause of the disease is a mutation in the PAX9 gene.

The 1q21.1 recurrent microdeletion itself does not appear to lead to a clinically recognizable syndrome as some persons with the deletion have no obvious clinical findings and others have variable findings that most commonly include microcephaly (50%), mild intellectual disability (30%), mildly dysmorphic facial features, and eye abnormalities (26%). Other findings can include cardiac defects, genitourinary anomalies, skeletal malformations, and seizures (~15%). Psychiatric and behavioral abnormalities can include autism spectrum disorders, attention deficit hyperactivity disorder, autistic features, and sleep disturbances.

SLC25A24 Fontaine progeroid syndrome is a multisystem connective tissue disorder characterized by poor growth, abnormal skeletal features, and distinctive craniofacial features with sagging, thin skin, and decreased subcutaneous fat suggesting an aged appearance that is most pronounced in infancy and improves with time. Characteristic radiographic features include turribrachycephaly with widely open anterior fontanelle, craniosynostosis, and anomalies of the terminal phalanges. Cardiovascular, genitourinary, ocular, and gastrointestinal abnormalities may also occur. To date, 13 individuals with a molecularly confirmed diagnosis of SLC25A24 Fontaine progeroid syndrome have been described.

Axenfeld-Rieger syndrome is primarily an eye disorder, although it can also affect other parts of the body. This condition is characterized by abnormalities of the front part of the eye, an area known as the anterior segment. For example, the colored part of the eye (the iris), may be thin or poorly developed. The iris normally has a single central hole, called the pupil, through which light enters the eye. People with Axenfeld-Rieger syndrome often have a pupil that is off-center (corectopia) or extra holes in the iris that can look like multiple pupils (polycoria). This condition can also cause abnormalities of the cornea, which is the clear front covering of the eye.\n\nAbout half of affected individuals develop glaucoma, a serious condition that increases pressure inside the eye. When glaucoma occurs with Axenfeld-Rieger syndrome, it most often develops in late childhood or adolescence, although it can occur as early as infancy. Glaucoma can cause vision loss or blindness.\n\nResearchers have described at least three types of Axenfeld-Rieger syndrome. The types, which are numbered 1 through 3, are distinguished by their genetic cause.\n\nThe signs and symptoms of Axenfeld-Rieger syndrome can also affect other parts of the body. Many affected individuals have distinctive facial features such as widely spaced eyes (hypertelorism); a flattened mid-face with a broad, flat nasal bridge; and a prominent forehead. The condition is also associated with dental abnormalities including unusually small teeth (microdontia) or fewer than normal teeth (oligodontia). Some people with Axenfeld-Rieger syndrome have extra folds of skin around their belly button (redundant periumbilical skin). Other, less common features can include heart defects, the opening of the urethra on the underside of the penis (hypospadias), narrowing of the anus (anal stenosis), and abnormalities of the pituitary gland that can result in slow growth.

Zlotogora-Ogur syndrome is an ectodermal dysplasia syndrome with characteristics of hair, skin and teeth anomalies, facial dysmorphism with cleft lip and palate, cutaneous syndactyly and, in some cases, intellectual disability.The prevalence is unknown but to date, less than 50 cases have been described in the literature. Caused by mutations in the gene PVRL1 (11q23-q24) which encodes nectin-1, the principal receptor used by alpha-herpesviruses to mediate entry into human cells. Transmission is autosomal recessive.

16p13.3 microduplication syndrome is a rare chromosomal anomaly syndrome resulting from a partial duplication of the short arm of chromosome 16 and manifesting with a variable phenotype which is mostly characterized by: mild to moderate intellectual deficit and developmental delay (particularly speech), normal growth, short, proximally implanted thumbs and other hand and feet malformations (such as camptodactyly, syndactyly, club feet), mild arthrogryposis and characteristic facies (upslanting, narrow palpebral fissures, hypertelorism, mid face hypoplasia, bulbous nasal tip and low set ears). Other reported manifestations include cryptorchidism, inguinal hernia and behavioral problems.

Cranioectodermal dysplasia (CED) is a ciliopathy with skeletal involvement (narrow thorax, shortened proximal limbs, syndactyly, polydactyly, brachydactyly), ectodermal features (widely spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity, abnormal nails), joint laxity, growth deficiency, and characteristic facial features (frontal bossing, low-set simple ears, high forehead, telecanthus, epicanthal folds, full cheeks, everted lower lip). Most affected children develop nephronophthisis that often leads to end-stage kidney disease in infancy or childhood, a major cause of morbidity and mortality. Hepatic fibrosis and retinal dystrophy are also observed. Dolichocephaly, often secondary to sagittal craniosynostosis, is a primary manifestation that distinguishes CED from most other ciliopathies. Brain malformations and developmental delay may also occur.

Multiple congenital anomalies-hypotonia-seizures syndrome-2 (MCAHS2) is an X-linked recessive neurodevelopmental disorder characterized by dysmorphic features, neonatal hypotonia, early-onset myoclonic seizures, and variable congenital anomalies involving the central nervous, cardiac, and urinary systems. Some affected individuals die in infancy (summary by Johnston et al., 2012). The phenotype shows clinical variability with regard to severity and extraneurologic features. However, most patients present in infancy with early-onset epileptic encephalopathy associated with developmental arrest and subsequent severe neurologic disability; these features are consistent with a form of developmental and epileptic encephalopathy (DEE) (summary by Belet et al., 2014, Kato et al., 2014). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. For a discussion of genetic heterogeneity of MCAHS, see MCAHS1 (614080). For a discussion of nomenclature and genetic heterogeneity of DEE, see 308350. For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).

CHST3-related skeletal dysplasia is characterized by short stature of prenatal onset, joint dislocations (knees, hips, radial heads), clubfeet, and limitation of range of motion that can involve all large joints. Kyphosis and occasionally scoliosis with slight shortening of the trunk develop in childhood. Minor heart valve dysplasia has been described in several persons. Intellect and vision are normal.

Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by Huber and Cormier-Daire, 2012 and Schmidts et al., 2013). There is phenotypic overlap with the cranioectodermal dysplasias (Sensenbrenner syndrome; see CED1, 218330). For a discussion of genetic heterogeneity of short-rib thoracic dysplasia, see SRTD1 (208500).

Coffin-Siris syndrome (CSS) is classically characterized by aplasia or hypoplasia of the distal phalanx or nail of the fifth and additional digits, developmental or cognitive delay of varying degree, distinctive facial features, hypotonia, hirsutism/hypertrichosis, and sparse scalp hair. Congenital anomalies can include malformations of the cardiac, gastrointestinal, genitourinary, and/or central nervous systems. Other findings commonly include feeding difficulties, slow growth, ophthalmologic abnormalities, and hearing impairment.

MED12-related disorders include the phenotypes of FG syndrome type 1 (FGS1), Lujan syndrome (LS), X-linked Ohdo syndrome (XLOS), Hardikar syndrome (HS), and nonspecific intellectual disability (NSID). FGS1 and LS share the clinical findings of cognitive impairment, hypotonia, and abnormalities of the corpus callosum. FGS1 is further characterized by absolute or relative macrocephaly, tall forehead, downslanted palpebral fissures, small and simple ears, constipation and/or anal anomalies, broad thumbs and halluces, and characteristic behavior. LS is further characterized by large head, tall thin body habitus, long thin face, prominent nasal bridge, high narrow palate, and short philtrum. Carrier females in families with FGS1 and LS are typically unaffected. XLOS is characterized by intellectual disability, blepharophimosis, and facial coarsening. HS has been described in females with cleft lip and/or cleft palate, biliary and liver anomalies, intestinal malrotation, pigmentary retinopathy, and coarctation of the aorta. Developmental and cognitive concerns have not been reported in females with HS. Pathogenic variants in MED12 have been reported in an increasing number of males and females with NSID, with affected individuals often having clinical features identified in other MED12-related disorders.

Axenfeld-Rieger syndrome is an autosomal dominant disorder of morphogenesis that results in abnormal development of the anterior segment of the eye, and results in blindness from glaucoma in approximately 50% of affected individuals (Fitch and Kaback, 1978). Systemic anomalies are associated, including dental hypoplasia, failure of involution of periumbilical skin, and maxillary hypoplasia (Alkemade, 1969). Genetic Heterogeneity of Axenfeld-Rieger Syndrome Linkage studies indicate that a second type of Axenfeld-Rieger syndrome maps to chromosome 13q14 (RIEG2; 601499). A third form of Axenfeld-Rieger syndrome (RIEG3; 602482) is caused by mutation in the FOXC1 gene (601090) on chromosome 6p25. See 109120 for a form of Axenfeld-Rieger syndrome associated with partially absent eye muscles, hydrocephalus, and skeletal abnormalities.

Hypohidrotic ectodermal dysplasia (HED) is characterized by hypotrichosis (sparseness of scalp and body hair), hypohidrosis (reduced ability to sweat), and hypodontia (congenital absence of teeth). The cardinal features of classic HED become obvious during childhood. The scalp hair is thin, lightly pigmented, and slow growing. Sweating, although present, is greatly deficient, leading to episodes of hyperthermia until the affected individual or family acquires experience with environmental modifications to control temperature. Only a few abnormally formed teeth erupt, at a later-than-average age. Physical growth and psychomotor development are otherwise within normal limits. Mild HED is characterized by mild manifestations of any or all the characteristic features.

Hypohidrotic ectodermal dysplasia (HED) is characterized by hypotrichosis (sparseness of scalp and body hair), hypohidrosis (reduced ability to sweat), and hypodontia (congenital absence of teeth). The cardinal features of classic HED become obvious during childhood. The scalp hair is thin, lightly pigmented, and slow growing. Sweating, although present, is greatly deficient, leading to episodes of hyperthermia until the affected individual or family acquires experience with environmental modifications to control temperature. Only a few abnormally formed teeth erupt, at a later-than-average age. Physical growth and psychomotor development are otherwise within normal limits. Mild HED is characterized by mild manifestations of any or all the characteristic features.

ADNP-related disorder is characterized by hypotonia, severe speech and motor delay, mild-to-severe intellectual disability, and characteristic facial features (prominent forehead, high anterior hairline, wide and depressed nasal bridge, and short nose with full, upturned nasal tip) based on a cohort of 78 individuals. Features of autism spectrum disorder are common (stereotypic behavior, impaired social interaction). Other common findings include additional behavioral problems, sleep disturbance, brain abnormalities, seizures, feeding issues, gastrointestinal problems, visual dysfunction (hypermetropia, strabismus, cortical visual impairment), musculoskeletal anomalies, endocrine issues including short stature and hormonal deficiencies, cardiac and urinary tract anomalies, and hearing loss.

Congenital symmetric circumferential skin creases is characterized by the folding of excess skin, which leads to ringed creases, primarily of the limbs. Affected individuals also exhibit intellectual disability, cleft palate, and dysmorphic features (summary by Isrie et al., 2015). For a discussion of genetic heterogeneity of congenital symmetric circumferential skin creases, see CSCSC1 (156610).

Selective tooth agenesis-9 (STHAG9) is an autosomal dominant disorder characterized by agenesis of various teeth. Other features include taurodontism, microdontia, short tooth roots, sparse and slow-growing hair, and dry and itchy skin (Kantaputra et al., 2015). For a general phenotypic description and a discussion of genetic heterogeneity of selective tooth agenesis, see STHAG1 (106600).

Any tooth agenesis in which the cause of the disease is a mutation in the WNT10B gene.

Bone marrow failure syndrome-3 is an autosomal recessive disorder characterized by onset of pancytopenia in early childhood. Patients may have additional variable nonspecific somatic abnormalities, including poor growth, microcephaly, and skin anomalies (summary by Tummala et al., 2016). BMFS3 has a distinct phenotype and may include features that overlap with Shwachman-Diamond syndrome (SDS1; 260400), such as pancreatic insufficiency and short stature, and with dyskeratosis congenita (see, e.g., DKCA1, 127550), such as dental and hair abnormalities and shortened telomeres. In addition, some patients may have joint and skeletal abnormalities, impaired development, and retinal dysplasia (summary by D'Amours et al., 2018). For a discussion of genetic heterogeneity of BMFS, see BMFS1 (614675).

Cole-Carpenter syndrome is characterized by bone fragility, craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features (Cole and Carpenter, 1987). Genetic Heterogeneity of Cole-Carpenter Syndrome Cole-Carpenter syndrome-2 (CLCRP2; 616294) is caused by mutation in the SEC24D gene (607186).

CDK13-related disorder, reported in 43 individuals to date, is characterized in all individuals by developmental delay / intellectual disability (DD/ID); nearly all individuals older than age one year display impaired verbal language skills (either absent or restricted speech). Other common findings are recognizable facial features in some individuals, behavioral problems (autism spectrum disorder or autistic traits/stereotypies, attention-deficit/hyperactivity disorder), feeding difficulties in infancy, structural cardiac defects, and seizures.

Congenital heart defects and ectodermal dysplasia (CHDED) is a rare disorder characterized by these cardinal features, with additional variable features of microcephaly, craniofacial or skeletal dysmorphism, feeding difficulties, or hypotonia (Sifrim et al., 2016).

Craniometadiaphyseal dysplasia (CRMDD) is characterized clinically by macrocephaly with frontal prominence, dental hypoplasia, and increased bone fragility. Diagnostic radiologic features include thin bones in the superior part of calvaria with prominent wormian bones, diaphyseal widening of the long tubular bones in early childhood with wide undermineralized metaphyses in older individuals, widened ribs and clavicles, and broadening of short tubular bones with increased transparency and thin cortices (summary by Dhar et al., 2010).

Branchiootorenal spectrum disorder (BORSD) is characterized by malformations of the outer, middle, and inner ear associated with conductive, sensorineural, or mixed hearing impairment, branchial fistulae and cysts, and renal malformations ranging from mild renal hypoplasia to bilateral renal agenesis. Some individuals progress to end-stage renal disease (ESRD) later in life. Extreme variability can be observed in the presence, severity, and type of branchial arch, otologic, audiologic, and renal abnormality from right side to left side in an affected individual and also among individuals in the same family.

The cartilage-hair hypoplasia – anauxetic dysplasia (CHH-AD) spectrum disorders are a continuum that includes the following phenotypes: Metaphyseal dysplasia without hypotrichosis (MDWH). Cartilage-hair hypoplasia (CHH). Anauxetic dysplasia (AD). CHH-AD spectrum disorders are characterized by severe disproportionate (short-limb) short stature that is usually recognized in the newborn, and occasionally prenatally because of the short extremities. Other findings include joint hypermobility, fine silky hair, immunodeficiency, anemia, increased risk for malignancy, gastrointestinal dysfunction, and impaired spermatogenesis. The most severe phenotype, AD, has the most pronounced skeletal phenotype, may be associated with atlantoaxial subluxation in the newborn, and may include cognitive deficiency. The clinical manifestations of the CHH-AD spectrum disorders are variable, even within the same family.

The Meier-Gorlin syndrome is a rare disorder characterized by severe intrauterine and postnatal growth retardation, microcephaly, bilateral microtia, and aplasia or hypoplasia of the patellae (summary by Shalev and Hall, 2003). While almost all cases have primordial dwarfism with substantial prenatal and postnatal growth retardation, not all cases have microcephaly, and microtia and absent/hypoplastic patella are absent in some. Despite the presence of microcephaly, intellect is usually normal (Bicknell et al., 2011). Genetic Heterogeneity of Meier-Gorlin Syndrome Most forms of Meier-Gorlin syndrome are autosomal recessive disorders, including Meier-Gorlin syndrome-1; Meier-Gorlin syndrome-2 (613800), caused by mutation in the ORC4 gene (603056) on chromosome 2q23; Meier-Gorlin syndrome-3 (613803), caused by mutation in the ORC6 gene (607213) on chromosome 16q11; Meier-Gorlin syndrome-4 (613804), caused by mutation in the CDT1 gene (605525) on chromosome 16q24; Meier-Gorlin syndrome-5 (613805), caused by mutation in the CDC6 gene (602627) on chromosome 17q21; Meier-Gorlin syndrome-7 (617063), caused by mutation in the CDC45L gene (603465) on chromosome 22q11; and Meier-Gorlin syndrome-8 (617564), caused by mutation in the MCM5 gene (602696) on chromosome 22q12. An autosomal dominant form of the disorder, Meier-Gorlin syndrome-6 (616835), is caused by mutation in the GMNN gene (602842) on chromosome 6p22.

Coffin-Siris syndrome (CSS) is classically characterized by aplasia or hypoplasia of the distal phalanx or nail of the fifth and additional digits, developmental or cognitive delay of varying degree, distinctive facial features, hypotonia, hirsutism/hypertrichosis, and sparse scalp hair. Congenital anomalies can include malformations of the cardiac, gastrointestinal, genitourinary, and/or central nervous systems. Other findings commonly include feeding difficulties, slow growth, ophthalmologic abnormalities, and hearing impairment.

Any BAFopathy in which the cause of the disease is a mutation in the BCL11B gene.

Trichohepatoneurodevelopmental syndrome is a complex multisystem disorder characterized by woolly or coarse hair, liver dysfunction, pruritus, dysmorphic features, hypotonia, and severe global developmental delay (Morimoto et al., 2018).

A rare genetic metabolic liver disease with characteristics of progressive neurodegeneration, cutaneous abnormalities including varying degrees of ichthyosis or seborrheic dermatitis, and systemic iron overload. Patients manifest with infantile-onset seizures, encephalopathy, abnormal eye movements, axial hypotonia with peripheral hypertonia, brisk reflexes, cortical blindness and deafness, myoclonus and hepato/splenomegaly, as well as oral manifestations including microdontia, widely spaced and pointed teeth with delayed eruption and gingival overgrowth.

Galloway-Mowat syndrome is a phenotypically heterogeneous disorder characterized by neurodevelopmental defects combined with renal-glomerular disease manifest as nephrotic syndrome and proteinuria. Most patients with GAMOS6 also have growth deficiency with variable microcephaly, and the renal disease may be age-dependent. Additional variable endocrine abnormalities have also been reported (summary by Braun et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of GAMOS, see GAMOS1 (251300).

Turnpenny-Fry syndrome (TPFS) is characterized by developmental delay, impaired intellectual development, impaired growth, and recognizable facial features that include frontal bossing, sparse hair, malar hypoplasia, small palpebral fissures and oral stoma, and dysplastic 'satyr' ears. Other common findings include feeding problems, constipation, and a range of brain, cardiac, vascular, and skeletal malformations (Turnpenny et al., 2018).

Rothmund-Thomson syndrome (RTS) is characterized by a rash that progresses to poikiloderma; sparse hair, eyelashes, and/or eyebrows; small size; skeletal and dental abnormalities; juvenile cataracts; and an increased risk for cancer, especially osteosarcoma. A variety of benign and malignant hematologic abnormalities have been reported in affected individuals. The rash of RTS typically develops between ages three and six months (occasionally as late as age two years) as erythema, swelling, and blistering on the face, subsequently spreading to the buttocks and extremities. The rash evolves over months to years into the chronic pattern of reticulated hypo- and hyperpigmentation, telangiectasias, and punctate atrophy (collectively known as poikiloderma) that persist throughout life. Hyperkeratotic lesions occur in approximately one third of individuals. Skeletal abnormalities can include radial ray defects, ulnar defects, absent or hypoplastic patella, and osteopenia.

EDFAOB is characterized by linear hypopigmentation and craniofacial asymmetry in association with ocular, dental, and acral anomalies. Brain imaging has revealed some abnormalities, including diffuse cystic leukoencephalopathy and mildly enlarged lateral ventricles, but patients show no intellectual or neurologic impairment (Vabres et al., 2019).

Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.

Blepharophimosis-impaired intellectual development syndrome (BIS) is a congenital disorder characterized by a distinct facial appearance with blepharophimosis and global development delay. Affected individuals have delayed motor skills, sometimes with inability to walk, and impaired intellectual development with poor or absent speech; some patients show behavioral abnormalities. There are recognizable facial features, including epicanthal folds, sparse eyebrows, broad nasal bridge, short nose with downturned tip, and open mouth with thin upper lip. Other more variable features include distal skeletal anomalies, feeding difficulties with poor growth, respiratory infections, and hypotonia with peripheral spasticity (summary by Cappuccio et al., 2020).

Neurofacioskeletal syndrome with or without renal agenesis (NFSRA) is characterized by developmental delay and/or intellectual disability; corpus callosum hypoplasia or agenesis; facial dysmorphism, including upslanting palpebral fissures, broad nasal tip, and wide mouth; and skeletal abnormalities, including short stature, scoliosis, and flexion contractures, with broad fingertips and/or toes. Renal agenesis, unilateral or bilateral, has also been observed in some patients (Schneeberger et al., 2020).

Onychodystrophy, osteodystrophy, impaired intellectual development, and seizures syndrome (OORS) is an autosomal recessive syndromic developmental disorder characterized by global developmental delay with impaired intellectual development, dysmorphic facial features, and hypoplastic terminal phalanges and nails. Patients have seizures or tonic posturing. The disorder is associated with a defect in GPI anchoring of membrane-bound proteins (summary by Salian et al., 2021). For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293). See also DOORS syndrome (220500), which shows some overlapping clinical features.

Short-rib thoracic dysplasia-21 (SRTD21) is characterized by rhizomelic limb shortening with bowing of long bones and metaphyseal abnormalities, narrow chest with short broad ribs, and trident pelvis. Other features include hypotonia and global developmental delay, with corpus callosum hypoplasia and cerebellar vermis abnormalities on brain imaging, which may show the 'molar tooth' sign (Hammarsjo et al., 2017). For a general phenotypic description and discussion of genetic heterogeneity of SRTD, see SRTD1 (208500). Mutation in the KIAA0753 gene also causes orofaciodigital syndrome (OFD15; 617127) and Joubert syndrome (JBTS28; 619476), phenotypes with features overlapping those of SRTD21.

Developmental delay with variable neurologic and brain abnormalities (DENBA) is characterized most often by motor and speech delay apparent from early childhood. Most patients have delayed walking and variably impaired intellectual development. Additional neurologic features may include seizures, spasticity, and ocular abnormalities. Brain imaging often shows thin corpus callosum and may show white matter atrophy, myelination abnormalities, or enlarged ventricles. The severity of the disorder and clinical manifestations are highly variable (summary by Malhotra et al., 2021).

HH26 is characterized by micropenis and cryptorchidism at birth in male patients, and absent puberty and anosmia in male or female patients. Some affected individuals also exhibit craniosynostosis (Davis et al., 2020). Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism can be caused by an isolated defect in gonadotropin-releasing hormone (GNRH; 152760) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (summary by Raivio et al., 2007). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia (HH).' For a discussion of genetic heterogeneity of hypogonadotropic hypogonadism with or without anosmia as well as a discussion of oligogenicity of this disorder, see 147950.

Teebi hypertelorism syndrome-2 (TBHS2) is characterized primarily by hypertelorism, prominent forehead, thick and broad eyebrows, and short nose with depressed nasal root and broad nasal tip. Other features include thin upper lip, small chin with horizontal crease, and high or cleft palate. Developmental delay and/or impaired intellectual development have been observed in some patients (Li et al., 2021). For a general phenotypic description and a discussion of genetic heterogeneity of Teebi hypertelorism syndrome, see TBHS1 (145420).

Developmental and epileptic encephalopathy-100 (DEE100) is a severe neurologic disorder characterized by global developmental delay and onset of variable types of seizures in the first months or years of life. Most patients have refractory seizures and show developmental regression after seizure onset. Affected individuals have ataxic gait or inability to walk and severe to profoundly impaired intellectual development, often with absent speech. Additional more variable features may include axial hypotonia, hyperkinetic movements, dysmorphic facial features, and brain imaging abnormalities (summary by Schneider et al., 2021). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Dworschak-Punetha neurodevelopmental syndrome (DWOPNED) is an autosomal recessive disorder characterized mainly by global developmental delay and mildly impaired intellectual development (IQ range 77 to 85), often with behavioral abnormalities, including autism spectrum disorder and hyperactivity. Some affected individuals may have only speech delay or behavioral manifestations. More variable additional features include optic disc hypoplasia, ptosis, hypo- or hyperpigmented skin lesions, nonspecific dysmorphic facial features, and brain imaging abnormalities of the ventricles or corpus callosum. Of note, not all patients exhibit all features, and there is significant inter- and intrafamilial phenotypic variability (Dworschak et al., 2021).

Primordial dwarfism-immunodeficiency-lipodystrophy syndrome (PDIL) is characterized by pre- and postnatal growth restriction, with extreme microcephaly, short stature, and absence of subcutaneous fat. There is also significant hematologic/immune dysfunction, with hypo- or agammaglobulinemia, as well as lymphopenia, anemia, and thrombocytopenia, and most affected individuals succumb to infection in early childhood (Parry et al., 2020).

Orofaciodigital syndrome XIX (OFD19) is an autosomal recessive ciliopathy characterized by tongue nodules; dental anomalies including congenital absence or abnormal shape of incisors; narrow, high-arched or cleft palate; retrognathia; and digital anomalies. Some patients have notching of the upper or lower lip (Iturrate et al., 2022).

Lacrimoauriculodentodigital syndrome-2 (LADD2) is a multiple congenital anomaly disorder mainly affecting lacrimal glands and ducts, salivary glands and ducts, ears, teeth, and distal limb segments (summary by Rohmann et al., 2006).

Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-3 (TEBIVANED3) is characterized by global developmental delay with poor overall growth, impaired intellectual development, and speech difficulties. More variable features include hypotonia, microcephaly, and dysmorphic facies. The severity and manifestations of the disorder are highly variable (Tessadori et al., 2022). For a discussion of genetic heterogeneity of Tessadori-Bicknell-van Haaften neurodevelopmental disorder, see TEBIVANED1 (619758).

Lacrimoauriculodentodigital syndrome-1 (LADD1) is a multiple congenital anomaly disorder mainly affecting lacrimal glands and ducts, salivary glands and ducts, ears, teeth, and distal limb segments (summary by Rohmann et al., 2006). Genetic Heterogeneity of Lacrimoauriculodentodigital Syndrome LADD syndrome-2 (LADD2; 620192) is caused by mutation in the FGFR3 gene (134934) on chromosome 4p16, and LADD syndrome-3 (LADD3; 620193) is caused by mutation in the FGF10 gene, an FGFR ligand, on chromosome 5p12.